The present invention generally relates to silicon-containing chain extenders and their use in the preparation of polyurethane elastomeric compositions having improved properties. These polyurethane compositions are useful for a variety of applications, in particular the manufacture of medical devices, articles or implants which contact living tissues or bodily fluids.
Polyurethane elastomers are amongst the best performing synthetic polymers in medical implant applications. Their excellent mechanical properties coupled with relatively good biostability make them the choice materials for a number of medical implants including cardiac pacemakers, catheters, implantable prostheses, cardiac assist devices, heart valves and vascular grafts. The excellent mechanical properties of polyurethane elastomers are attributed to their two phase morphology resulting from microphase separation of soft and hard segments. In polyurethanes used for medical implants, the soft segment is typically formed from a polyether macrodiol such as poly(tetramethylene oxide) (PTMO) while the hard segment is derived from a diisocyanate such as 4,4xe2x80x2-methylenediphenyl diisocyanate (MDI) and a diol chain extender such as 1,4-butanediol (BDO).
The diol chain extender which is used to link up diisocyanates is a relatively small difunctional molecule of molecular weight between about 60 and 350. The structure of the chain extender makes a significant contribution to the physical properties of the polyurethane elastomers. The most commonly used diol chain extender is 1,4-butanediol.
Despite the long term use of polyurethane elastomers for applications such as cardiac pacemakers, in some cases the polyurethanes biodegrade causing surface or deep cracking, stiffening, erosion or the deterioration of mechanical properties such as flexural strength1. Elastomers with high flexibility and low Shore A Durometer hardness in particular degrade faster than the harder and more rigid grades. It is generally hypothesized that the degradation is primarily an in vivo oxidation process involving the polyether soft segment. The currently used medical polyurethanes are polyether-based and the most vulnerable site for degradation is the methylene group alpha to the ether oxygen2 of the soft segment. Polyurethanes prepared with a lower amount of polyether component generally exhibit improved degradation resistance. However, such materials typically have high elastic modulus and are difficult to process making them less desirable for many implant applications. Pinchuk has recently reviewed the biostability of polyurethanes3.
Non-PTMO based polyurethane formulations which show significantly improved in vivo degradation resistance as demonstrated by animal implant experiments have also recently been disclosed in the patent literature. These include polyurethane formulations based on polycarbonate macrodiols disclosed in U.S. Pat. No. 5,133,742 (Pinchuk) and U.S. Pat. No. 5,254,662 (Szycher) and polyether macrodiols with fewer ether linkages in U.S. Pat. No. 4,875,308 (Meijs et al). The aforementioned patents do not disclose polyurethane formulations which provide materials having flexural modulus, hardness and biostability comparable to those of silicon rubber while retaining high tensile strength, abrasion resistance and tear strength of typical polyurethane elastomers. Although the compositions disclosed in U.S. Pat. No. 5,254,662 provide materials with low elastic modulus and high tensile strength, since those compositions are based on polycarbonate macrodiols and aliphatic diisocyanates, their degradation resistance under in vivo conditions is questionable. Hergenrother et al4 have demonstrated by animal implant experiments that aliphatic diisocyanate based polyurethanes degrade more than the aromatic diisocyanate based polyurethanes. There are also no examples provided in U.S. Pat. No. 5,254,662 to demonstrate the biostability of the disclosed low modulus elastomer compositions.
The conventional method of preparing polyurethane elastomers with low hardness and modulus is by formulation changes so as to have a relatively higher percentage of the soft segment component. However, the materials made this way generally have very poor mechanical properties and biostability. For example, it is reported2.1 that Pellethane 2363-80A (Registered Trade Mark) which has a higher percentage of soft segment than that in the harder grade Pellethane 2363-55D (Registered Trade Mark), is significantly more prone to stress cracking in the biological environment. However, these reports do not disclose methods for formulating polyurethanes with hardness lower than 80 A while retaining good biostability and mechanical properties. Despite the good stability of silicone rubber in biological environments, its use in the medical implant area is limited by poor properties such as low abrasion resistance and low tensile and tear strengths.
Although the aforementioned non-PTMO based polyurethane elastomers address the issue of biostability, they do not provide methods of formulating polyurethanes having properties such as flexibility and biostability comparable to those of silicone rubber. The formulations disclosed in the above patents (except U.S. Pat. No. 5,254,662) typically have hardness in excess of Shore 80 A.
A requirement accordingly exists to develop polyurethanes having properties such as low durometer hardness, low flexural modulus, good processability and high resistance to degradation, without the disadvantages of silicone rubber such as poor tensile strength, abrasion resistance and tear strength. Such polyurethanes should also preferably have a good biostability for applications such as pacemaker leads, vascular grafts, heart valves and the like.
According to one aspect of the present invention there is provided a chain extender including a silicon-containing diol of the formula (I): 
wherein
R1, R2, R3, R4, R5, and R6 are the same or different and selected from an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical;
R7 is a divalent linking group or an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical; and
n is 0 or greater, preferably 2 or less.
The present invention also provides use of the diol of the formula (I) defined above as a chain extender.
The present invention further provides the diol of the formula (I) as defined above when used as a chain extender.
The hydrocarbon radical for substituents R1, R2, R3 and R4 may include alkyl, alkenyl, alkynyl, aryl or heterocyclyl radicals. It will be appreciated that the equivalent radicals may be used for substituents R5, R6 and R7 except that the reference to alkyl, alkenyl and alkynyl should be to alkylene, alkenylene and alkynylene, respectively. In order to avoid repetition, only detailed definitions of alkyl, alkenyl and alkynyl are provided hereinafter.
The term xe2x80x9calkylxe2x80x9d denotes straight chain, branched or mono- or poly-cyclic alkyl, preferably C1-12 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, pentyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyloctyl, 1-, 2-, 3-, 4- or 5-ethylheptyl 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1,2-pentylheptyl and the like. Examples of cyclic alkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term xe2x80x9calkenylxe2x80x9d denotes groups formed from straight chain, branched or mono- or poly-cyclic alkenes including ethylenically mono- or poly-unsaturated alkyl or cycloalkyl groups as defined above, preferably C2-12 alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methylcyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3 heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl, 1,3,5,7-cycloocta-tetraenyl and the like.
The term xe2x80x9calkynylxe2x80x9d denotes groups formed from straight chain, branched, or mona or poly-cyclic alkynes. Examples of alkynyl include ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 10-undecynyl, 4-ethyl-1-octyn-3-yl, 7-dodecynyl, 9-dodecynyl, 10-dodecynyl, 3-methyl-1-dodecyn-3-yl, 2-tridecynyl, 11-tridecynyl, 3-tetradecynyl, 7-hexadecynyl, 3-octadecynyl and the like.
The term xe2x80x9carylxe2x80x9d denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbons. Examples of aryl include phenyl, biphenyl, terphenyl, quatemphenyl, phenoxyphenyl, naphthyl, tetahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenantrenyl and the like.
The term xe2x80x9cheterocyclylxe2x80x9d denotes mono- or poly-cyclic heterocyclyl groups containing at least one heteroatom selected from nitrogen, sulphur and oxygen. Suitable heterocyclyl groups include N-containing heterocyclic groups, such as, unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperdino or piperazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, such as, pyranyl or furyl unsaturated 3 to 6-membered hetermonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, isoazolyl or oxadiazolyl; saturated 3 to 6membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as thiazolyl or thiadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiadiazolyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl or benzothiadiazolyl.
In this specification, xe2x80x9coptionally substitutedxe2x80x9d means that a group may or may not be further substituted with one or more groups selected from oxygen, nitrogen, sulphur, alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, aryloxy, carboxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, azido, amino, alkylamino, alkenylamino, alkynylamino, arylamino, benzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, acyloxy, aldehydo, alkylsulphonyl, arylsulphonyl, alkylsulphonylamino, arylsulphonylamino, aIkylsulphonyloxy, arylsulphonyloxy, heterocyclyl, heterocycloxy, heterocyclylamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy, mercapto, alkylthio, arylthio, acylthio and the like.
Term xe2x80x9dhaloxe2x80x9d denotes fluoro, chloro, bromo, or iodo, preferably fluoro. Examples of suitable fluoro radicals include trifluoropropyl, pentafluorobutyl, and heptafluoropropyl.
Suitable divalent linking groups for R7 include 0, S and NR wherein R is hydrogen or an optionally substituted straight chain, branched or cyclic, saturated or unsaturated hydrocarbon radical.
Preferred silicon-containing diols are 1,3-bis(4hydroxybutyl)tetramethyl disiloxane (compound of formula (I) wherein R1, R2, R3 and R4 are methyl, R5 and R6 are butyl and R7 is O), 1,4-bis(3-hydroxypropyl)tetramethyl disilylethylene (compound of formula (I) wherein R1, R2, R3 and R4 are methyl, R5 and R6 are propyl and R7 is ethylene) and 1-4-bis(3-hydroxypropyl)tetramethyl disiloxane.
The silicon-containing diol chain extenders can be conveniently prepared by methods reported in the literature6. Some of these compounds such as 1,3-bis(3-hydroxypropyl)tetramethyl disilylethylene (BPTD) and 1,3-bis(4-hydroxybutyl) tetramethyl disiloxane (BHTD) are available commercially. Others can be prepared by using hydrosilylation reaction of the appropriate hydroxy alkene and 1,1,3,3,-tetramethyldisiloxane using a catalyst such as Wilkinson""s catalyst
Some of the diols of formula (I) are novel per se. Thus, the present invention also provides a silicon-containing diol of the formula (I) defined above wherein R7 is ethylene.
In a preferred embodiment, the diol of the formula (I) defined above is combined with a chain extender known in the art of polyurethane manufature.
According to another aspect of the present invention provides a chain extender composition including a silicone-containing diol of the formula (I) defined above and a chain extender known in the art of polyurethane manufacture.
The present invention also provides use of the composition defined above as a chain extender.
The present invention further provides the composition defined above when used as a chain extender.
The chain extender known in the art of polyurethane manufacture is preferably selected from 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,12-dodecanediol, 1,4-cyclohexanedimethanol, p-xylene glycol and 1,4-bis(2-hydroxyethoxy)benzene. 1,4 butanediol is particularly preferred.
The silicon chain extender and the known chain extender can be used in a range of molar proportions with decreasing tensile properties as the molar percentage of the silicon chain extender increases in the mixture. A preferred molar percentage of silicon chain extender is about 1 to about 50%, more preferably about 40%.
Although the preferred chain extender composition contains one known chain extender and one silicon-containing diol, it will be understood that mixtures containing more than one known chain extender and diol may be used in the chain extender composition.
The chain extender and chain extender composition of the present invention are particularly useful in preparing polyurethane elastomeric compositions.
According to a still further aspect of the present invention there is provided a polyurethane elastomeric composition which includes a segment derived from the chain extender or chain extender composition defined above.
The polyurethane elastomeric compositions of the present invention may be prepared by any suitable known technique. A preferred method involves mixing the chain extender or chain extender composition with a soft segment macrodiol and then reacting this mixture with a diisocyanate. The initial ingredients are preferably mixed at a temperature in the range of about 45 to about 100xc2x0 C., more preferably about 60 to about 80xc2x0 C. If desired, a catalyst such as dibutyl tin dilaurate at a level of about 0.001 to about 0.5 wt % based on the total ingredients may be added to the initial mixture. The mixing may occur in conventional apparatus or within the confines of a reactive extruder or continuous reactive injection molding machine.
Alternatively, the polyurethanes may be prepared by the prepolymer method which involves reacting a diisocyanate with the soft segment macrodiol to form a prepolymer having terminal reactive diisocyanate groups. The prepolymer is then reacted with the chain extender or chain extender composition.
Thus, the polyurethane elastomeric composition of the present invention may be further defined as comprising a reaction product of:
(i) a soft segment macrodiol;
(ii) a diisocyanate; and
(iii) the chain extender or chain extender composition defined above.
The soft segment macrodiol may be of any suitable type known in the art of polyurethane manufacture. Examples include polyethers, polyesters, polysiloxanes, polycarbonates or mixtures thereof Preferably, the soft segment is derived from a polysiloxane macrodiol and a polyether macrodiol.
A suitable polysiloxane is polydimethyl siloxane (PDMS). The polysiloxane macrodiols may be obtained as commercially available products such as X-22-160AS from Shin Etsu or prepared according to known procedures7. The preferred molecular weight range of the polysiloxane macrodiol is about 200 to about 5000, preferably about 300 to about 3000.
Suitable polyether macrodiols include those represented by the formula (II)
HOxe2x80x94[(CH2)mxe2x80x94O]pxe2x80x94Hxe2x80x83xe2x80x83(II)
wherein
m is an integer of 4 or more, preferably 5 to 18; and
p is an integer of 2 to 50.
Although conventional polyether macrodiols such as PTMO can be used, the more preferred macrodiols and their preparation are described in Gunatillake et al8 and U.S. Pat. No. 5,403,912. Polyethers such as PHMO described in these references are more hydrophobic than PTMO and are more compatible with polysiloxane macrodiols. The preferred molecular weight range of the polyether macrodiol is about 200 to about 5000, more preferably about 200 to about 1200.
Preferably, the diisocyanate is selected from one or more of 4,4xe2x80x2-methylenediphenyl diisocyanate MDI), methylene bis (cyclohexyl) diisocyanate (H12MDI), p-phenylene diisocyanate (p-PDI), trans-cyclohexane-1, 4diisocyanate (CHDI) or a mixture of the cis and trans isomers, 1,6-hexamethylene diisocyanate (DICH), 2,4-toluene diisocyanate (2,4-TDI) or its isomers or mixtures thereof p-tetramethylxylene diisocyanate (p-TMXDI) and m-tetramethylxylene diisocyanate (m-TMXDI). MDI is particularly preferred.
A particularly preferred polyurethane elatomeric composition of the present invention comprises a reaction product of:
(i) macrodiols including:
(a) polysiloxane macrodiol; and
(b) polyether macrodiol;
(ii) MDI; and
(iii) chain extender composition including 1,4-butanediol and a silicon chain extender selected from 1,3-bis(4-hydroxybutyl)tetramethyl disiloxane and 1,4-bis(3-hydroxypropyl)tetramethyl disilylethylene and 1-4-bis(3-hydroxypropyl)tetramethyl disiloxane.
Preferably, the silicon chain extender is present in an amount of about 40 mol % of the chain extender composition.
The methods described above do not cause premature phase separation and yield polymers that are compositionally homogeneous and transparent having high molecular weights. These methods also have the advantage of not requiring the use of any solvent to ensure that the soft and hard segments are compatible during synthesis.
The polyurethane may be processed by conventional methods such as extrusion, injection and compression moulding without the need of added processing waxes. If desired, however, conventional polyurethane processing additives such as. catalysts, antioxidants, stablisers, lubricants, dyes, pigments, inorganic and/or organic fillers and reinforcing materials can be incorporated into the polyurethane during preparation. Such additives are preferably added to the soft segment macrodiol.
The soft segment macrodiol, diisocyanate and the chain extender or chain extender composition may be present in certain preferred proportions. The preferred level of hard segment (i.e. diisocyanate and chain extender) in the composition is about 40 to about 60 wt %. The weight ratio of polysiloxane to polyether in the preferred soft segment may be in the range of from 1:99 to 99:1. A particularly preferred ratio of polysiloxane to polyether which provides increased degradation resistance, stability and clarity is 80:20.
The polyurethane elastomeric composition of the present invention is particularly useful in preparing materials having good mechanical properties, in particular biomaterials.
According to another aspect of the present invention there is provided a material. having improved mechanical properties, clarity, processability and/or degradation resistance comprising a polyurethane elastomeric composition which includes a chain extender or chain extender composition defined above.
The present invention also provides use of the polyurethane elastomeric composition defined above as a material having improved mechanical properties, clarity, processability and/or degradation resistance.
The present invention fiber provides the polyurethane elastomeric composition defined above when used as a material having improved mechanical properties, clarity, processability and/or degradation resistance.
The mechanical properties which are improved include tensile strength, tear strength, abrasion resistance, Durometer hardness, flexural modulus and related measures of flexibility or elasticity.
The improved resistance to degradation includes resistance to free radical, oxidative, enzymatic and/or hydrolytic processes and to degradation when implanted as a biomaterial.
The improved processability includes ease of processing by casting such as solvent casting and by thermal means such as extrusion and injection molding, for example, low tackiness after extrusion and relative freedom from gels.
There is also provided a degradation resistant material which comprises the polyurethane elastomeric composition defined above.
The polyurethane elastomeric composition of the present invention shows good elastomeric properties. It should also have a good compatibility and stability in biological environments, particularly when implanted in vivo for extended periods of time.
According to another aspect of the present invention there is provided an in vivo degradation resistant material which comprises the polyurethane elastomeric composition defined above.
The polyurethane elastomeric composition may also be used as a biomaterial. The term xe2x80x9cbiomaterialxe2x80x9d is used herein in its broadest sense and refers to a material which is used in situations where it comes into contact with the cells and/or bodily fluids of living animals or humans.
The polyurethane elastomeric composition is therefore useful in manufacturing medical devices, articles or implants.
Thus, the present invention still further provides medical devices, articles or implants which are composed wholly or partly of the polyurethane elastomeric composition defined above.
The medical devices, articles or implants may include cardiac pacemakers, defibrillators and other electromedical devices, catheters, cannulas, implantable prostheses, cardiac assist devices, heart valves, vascular grafts, extra-corporeal devices, artificial organs, pacemaker leads, defibrillator leads, blood pumps, balloon pumps, A-V shunts, biosensors, membranes for cell encapsulation, drug delivery devices, wound dressings, artificial joints, orthopaedic implants, soft tissue replacements, intraocular lenses, optical devices, tissue engineering products, and ENT implants.
It will be appreciated that polyurethane elastomeric compositions having properties optimised for use in the construction of various medical devices, articles or implants will also have other non-medical applications. Such applications may include their use in the manufacture of artificial leather, shoe soles; cable sheathing; varnishes and coatings; structural components for pumps, vehicles, etc; mining ore screens and conveyor belts; laminating compounds, for example in glazing; textiles; separation membranes; sealants or as components of adhesives.
Thus, the present invention extends to the use of the polyurethane elastomeric composition defined above in the manufacture of devices or articles.
The present invention also provides devices or articles which are composed wholly or partly of the polyurethane elastomeric composition defined above.
The invention will now be described with reference to the following examples. These examples are not to be construed as limiting the invention in any way.